Lung disease of prematurity is a chronic lung disorder that is common among children born prematurely and is characterized by alveolar simplification, inflammation, and restrictive lung physiology. Despite advances in clinical ventilator management, the introduction of surfactant, and early low-dose hydrocortisone 1, there is a marked lack of adjunctive therapies. Assessing a tissues' metabolome is a powerful tool in identifying metabolic insufficiencies and developing targeted therapy to meet tissue metabolite insufficiencies. Previous metabolome studies provide limited insight into lung metabolism as plasma and urine surrogates from premature infants 2, 3 reflect the infants' overall metabolism and are at best biomarkers. Understanding the intersection between the lungs' metabolic needs and lung development while identifying the lungs' metabolic preferences and deficits in lung disease of prematurity could more effectively guide targeted therapy. Converting transplacental glucose into glycogen and fat storage drives fetal metabolism in utero. Following birth, a profound change in nutritional sources can unmask metabolic vulnerability as glycogen and fat stores are utilized as energy sources with ketone bodies and lactate serving as alternatives 4. In contrast to the term infant, availability of energy substrates in premature infants is insufficient, as adequate glycogen and fat stores are not accrued. Identifying those metabolic pathways and metabolites necessary for normal lung development and substrate deficiencies in compromised premature infants could yield new therapies targeted to replenish recognized insufficiencies. We hypothesize that mapping of the developing lungs' metabolic signature will provide distinct metabolic commitment steps and insufficiencies that regulate lung disease of prematurity. Our preliminary data supports a role for metabolism in distal lung development as analysis of lung tissue determined that: - neonatal lung development has a unique metabolic signature at the late saccular stage that strongly differs from lungs in the alveolar stage of development - the metabolic signature in a hyperoxia model of lung disease of prematurity significantly differs from normoxic littermate controls revealing metabolite deficiencies. Identification of the lungs' innate metabolic requirements during normal development and how prematurity alters the lungs' metabolic substrates necessary for development is the first essential step in determining how to replenish the required lung metabolites that support lung formation.